Muscle-secreted hormones (e.g., myokines) have been hypothesized to exist and exert autocrine, paracrine, or endocrine effects since skeletal muscle comprises the largest organ in the human body and exercise involving skeletal muscle contraction is known to have major metabolic and immunological effects (Pedersen (2010) J. Exp. Biol. 214:337-346). Despite decades of research focused on identifying myokines that can mimic the benefits of skeletal muscle-induced metabolic changes in organs such as adipose tissue and the immune system, very few such myokines have been discovered (Boström et al. (2012) Nature 481:463-468; Pedersen and Febbraio (2008) Physiol. Rev. 88:1379-1406). Exacerbating the paucity of known myokines having such beneficial therapeutic effects, the clinical need for such agents has never been greater.
For example, metabolic disorders comprise a collection of health disorders that increase the risk of morbidity and loss of quality of life afflicting greater than 50 million people in the United States. Such metabolic disorders, including diabetes, obesity, including central obesity (disproportionate fat tissue in and around the abdomen), atherogenic dyslipidemia (including a family of blood fat disorders, e.g., high triglycerides, low HDL cholesterol, and high LDL cholesterol that can foster plaque buildups in the vascular system, including artery walls), high blood pressure (130/85 mmHg or higher), insulin resistance or glucose intolerance (the inability to properly use insulin or blood sugar), a chronic prothrombotic state (e.g., characterized by high fibrinogen or plasminogen activator inhibitor-1 levels in the blood), and a chronic proinflammatory state (e.g., characterized by higher than normal levels of high-sensitivity C-reactive protein in the blood), are increasing in prevalence among the U.S. population.
Similarly, many myopathies are associated with inflammation of muscle (e.g., skeletal muscle) and are relatively prevalent among the general U.S. population. For example, Duchenne muscular dystrophy (DMD) affects 1 in 3,500 male births. Muscular dystrophies in general are a group of clinically and genetically heterogeneous myopathies characterized by progressive degenerative changes in the skeletal muscles. This group of genetically distinct disorders shares clinical and pathological characteristics but varies in severity, inheritance pattern, and molecular defects. For example, DMD is caused by mutations or deletions in the dystrophin gene (chromosome Xp21) leading to its reduction at the mRNA level and absence at the protein level. This loss of dystrophin causes a fragility of the muscle membrane resulting in repeated rounds of muscle fiber necrosis and regeneration associated with chronic inflammation, as well as progressive replacement of the muscle fibers by fibrosis and fat in the later stages of the disease. Studies in animal models and in DMD subjects seem to suggest that the immune system could also contribute to the lesions observed in the skeletal muscles. An increased inflammation has been described in dystrophin-deficient muscles, and it has been shown that the in vivo depletion of CD8+ T cells in the mdx mouse (the murine natural model of DMD) or the impairment of T cell cytotoxicity by the removal of perforin attenuates the disease. It has also been shown that irradiation of prenecrotic mdx mice improves or delays the pathological symptoms, presumably due to a decrease in the number of immune cells that can invade and kill the muscle. Finally, adoptive transfer of mdx immune cells in combination with muscle extracts resulted in muscle pathology in health murine recipients.
Thus, despite decades of scientific research, few effective myokine therapies have emerged to treat metabolic disorders and inflammatory disorders. Accordingly, there is a great need to identify molecular regulators of metabolic disorders and inflammatory-associated myopathy disorders, including the generation of diagnostic, prognostic, and therapeutic agents to effectively control such disorders in subjects.